Vaginal microbicides provide the best opportunity to develop a practical method for preventing sexual transmission of HIV. n-Docosanol is a saturated alcohol which inhibits the replication of enveloped viruses in vitro. The potential of this compound as a topical microbicide to prevent HIV transmission was tested in the SIV/rhesus macaque system. Six mature female rhesus macaques were treated by placing 12.5% n-Docosanol cream into the vagina before vaginal challenge with SIVmac251. Each animal was treated twice with the n-Docosanol cream prior to SIV challenge. The animals were then challenged with 1 ml of SIVmac251, and a third application of 1 ml n-Docosanol was placed in the vagina of the animals 1 hour after SIV challenge. Both naive control animals became persistently viremic and seroconverted to SIV antigens. One n-Docosanol treated animal became persistently SIV-infected and seropositive. The remaining 5 n-Docosanol treated animals remain uninfected and seronegative. These results demonstrate that n-Docosanol cream is capable of preventing the vaginal transmission of SIV and suggest that a preparation containing this compound may be useful in preventing sexual transmission of HIV. In order to determine if the SIV exposed animals were protected from subsequent SIV challenge, the animals were inoculated intravaginally with SIV. Five of 6 test animals and 2 of 3 controls became infected, indicating that the exposed animals were not protected from subsequent SIV exposures. *KEY*Vaginal microbicide, Sexual HIV transmission, Prevention